Chlorhexidine-Cyclamate Complexes and Oral Care Compositions Comprising the Same

ABSTRACT

The present disclosure provides a chlorhexidine-cyclamate complex having a formula [C 22 H 32 Cl 2 N 10 ][C 6 H 12 NO 3 S] 2  having antibacterial and antiplaque properties, together with oral care compositions comprising the complex, and methods of making and using these complexes and compositions.

BACKGROUND

Dental plaque is a soft deposit which forms on teeth and is comprised ofan accumulation of bacteria and bacterial by-products. Plaque adherestenaciously at the points of irregularity or discontinuity, e.g., onrough calculus surfaces, at the gum line and the like. Besides beingunsightly, plaque is implicated in the occurrence of gingivitis andother forms of periodontal disease.

A wide variety of antibacterial agents have been suggested in the art toretard plaque formation and the oral infection and dental diseaseassociated with plaque formation. For example, biguanide andbis-biguanide compounds such as chlorhexidine are well known to the artfor their antibacterial activity and have been used in oral compositionsto counter plaque formation by bacterial accumulation in the oralcavity. However, it is also well known that bis-biguanide compounds,when used as dental antiplaque agents cause unsightly staining of teeth.

In order for antiplaque activity to be imparted to the surface of atooth, the bis-biguanide must be deposited to at the surface of thetooth. This is normally achieved through brushing with a dentifrice orthrough swishing with a mouthwash containing the bis-biguanide. Oncedeposited at the surface of the tooth, the effect of the bis-biguanideon plaque is immediate. Through normal activities such as eating anddrinking, the contents of the dentifrice, including the bis-biguanideare washed away, which limits the term of its effectiveness. Inaddition, there is often a gap of many hours between brushing or use ofa suitable mouthwash, and plaque may accumulate during these interimperiods.

Thus, there is a need to deposit bis-biguanides, i.e., chlorhexidine, atthe surface of a tooth for an extended period of time. There is also aneed to develop a vehicle for a bis-biguanide that allows it to resistbeing washed away in the mouth through ordinary biological means.

BRIEF SUMMARY

Chlorhexidine is known as a potent antibacterial and antiplaque agentcommonly utilized in in oral care dentifrices. Sodium cyclamate is anartificial sweetener that is acceptable for use in consumer products,such as oral care compositions. The present disclosure provides achlorhexidine-cyclamate complex, which may interchangeably be referredto herein as CHC. The chemical structure of the complex is[C₂₂H₃₂Cl₂N₁₀][C₆H₁₂NO₃S]₂ or [C₂₂H₃₂Cl₂N₁₀][C₆H₁₂NO₃S]₂.H₂O. Thecomplex has key features that make it ideal for use in dentifricecompositions as an antibacterial or antiplaque agent.

The inventors have found that the CHC complex of the present disclosureis largely insoluble in water, and provides for an extended releaseprofile of chlorhexidine into the oral cavity. Thus, the presentdisclosure provides an antiplaque agent that acts on a tooth's surfaceduring a time period extending between brushing or use of a suitablemouthwash, so as to prevent plaque from accumulating.

The present disclosure thus provides CHC per se, as well as oral careproducts that deliver CHC to the oral cavity, i.e., to the surface ofthe teeth, and methods of making and using CHC. In one embodiment, thepresent disclosure provides oral care compositions that comprise CHC. Asthe CHC antibacterial properties, the present disclosure alsoencompasses other oral care compositions, for example mouth rinses ormouthwashes, comprising a CHC, e.g., any of Complex 1, et seq. and/orprecursors thereof. The disclosure further provides methods of reducingplaque comprising applying the composition to a surface of a tooth, andmethods of killing bacteria comprising contacting the bacteria with thecomposition.

Further areas of applicability of the present disclosure will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating preferred embodiments, are intended for purposes ofillustration only and are not intended to limit the scope of thedisclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will become more fully understood from thedetailed description and the accompanying drawings, wherein:

FIG. 1 depicts the mass spectrum (LC/MS) of the chlorhexidine cyclamatecomplex in methanol solution taken in positive ion mode;

FIG. 2 depicts the mass spectrum (LC/MS) of the chlorhexidine cyclamatecomplex in methanol solution taken in negative ion mode;

FIG. 3 depicts the tandem mass spectrum of cyclamate based on the parention represented at m/z: 682 in FIG. 2;

FIG. 4 depicts the tandem mass spectrum of cyclamate and chlorhexidinebased on the parent ion represented at m/z: 684 in FIG. 1;

FIG. 5 depicts the tandem mass spectrum of cyclamate and chlorhexidinebased on the parent ion represented at m/z: 863 in FIG. 1;

FIG. 6 depicts a ¹H NMR spectrum of the chlorhexidine cyclamate complexcrystal dissolved in deuterated DMSO;

FIG. 7 depicts a ¹H NMR COSY spectrum of the chlorhexidine cyclamatecomplex crystal dissolved in deuterated DMSO;

FIG. 8 depicts an enlarged section from FIG. 7; and

FIG. 9 depicts the crystalline structure of the chlorhexidine cyclamatecomplex determined by single-crystal X-ray diffraction measurement.

DETAILED DESCRIPTION

The following description of the preferred embodiment(s) is merelyexemplary in nature and is in no way intended to limit the disclosedcomplexes, its application, or uses.

The present disclosure therefore provides, in a first embodiment, achlorhexidine-cyclamate complex having the formula[C₂₂H₃₂Cl₂N₁₀][C₆H₁₂NO₃S]₂ (sometimes referred to herein as “CHC”),e.g.,

-   -   1.1. Complex 1 wherein the complex is formed from a mixture of        chlorhexidine and sodium cyclamate in a molar ratio of        chlorhexidine:sodium cyclamate of 1:1 to 1:3 (e.g., about 1:2).    -   1.2. Complex 1 or 1.1 in crystalline form.    -   1.3. Any of the foregoing complexes, wherein the complex is        anhydrous.    -   1.4. Any of the foregoing complexes, wherein the complex is in        the form of a hydrate, hemi-hydrate or polyhydrate (e.g.,        hydrate).    -   1.5. Any of the foregoing complexes in the form of a hydrate.    -   1.6. The complex of claims 1.4 or 1.5, having the formula        [C₂₂H₃₂Cl₂No][C₆H₁₂NO₃S]₂.H₂O.    -   1.7. Any of the foregoing complexes in crystalline form in a        P2₁/c space group.    -   1.8. Any of the foregoing complexes wherein the a biguanide        group in the chlorhexidine molecule is coordinated with a water        molecule and two cyclamate molecules.    -   1.9. Any of the foregoing complexes wherein both biguanide group        in the chlorhexidine molecule is coordinated with a water        molecule and two cyclamate molecules.    -   1.10. Any of the foregoing complexes having a structure wherein        a biguanide moiety of the chlorhexidine cation is coordinated by        two cyclamate ligands and a water ligand as shown in FIG. 9.    -   1.11. Any of the foregoing complexes wherein the        chlorhexidine-cyclamate complex forms a crystal in an aqueous        solution.    -   1.12. Complex 1.8, wherein the aqueous solution contains more        than 50 wt. % water, more than 60 wt. % water, more than 70 wt.        % water, or more than 80 wt. % water.    -   1.13. Complex 1.8 or 1.9, wherein the aqueous solution contains        84 wt % water, 3 wt. % ethanol, and 10 wt. % glycerin.    -   1.14. Any of the foregoing complexes wherein the        chlorhexidine-cyclamate complex forms as a precipitate in        aqueous solution.    -   1.15. Any of the foregoing complexes when crystalized from        aqueous ethanol.    -   1.16. Any of the foregoing complexes which forms a precipitate        upon increasing dilution with water.

In a further embodiment, the disclosure provides an oral carecomposition (Composition 2) for application to the oral cavity whichcomprises CHC, e.g., any of Complex 1, et seq., as described above, incombination with an orally acceptable carrier. For example, thedisclosure provides:

-   -   2.1 Composition 2 wherein the complex is formed from a mixture        of chlorhexidine and sodium cyclamate in a molar ratio of        chlorhexidine:sodium cyclamate of 1:1 to 1:3 (e.g., about 1:2).    -   2.2 Any of the foregoing complexes wherein the        chlorhexidine-cyclamate complex forms a crystal in an aqueous        solution.    -   2.3 Any of the foregoing complexes when crystalized from aqueous        ethanol.    -   2.4 Any of the foregoing compositions wherein CHC is complex is        formed, in whole or in part, in situ from chlorhexidine and        sodium cyclamate.    -   2.5 Any of the foregoing compositions comprising CHC in an        amount of 0.01 to 40% by weight of the composition.    -   2.6 Any of the foregoing compositions wherein the composition is        in the form of a dentifrice, gel or mouthwash

The disclosure further provides methods of killing bacteria comprisingcontacting the bacteria with an antibacterially effective amount of aCHC, e.g., any of Complex 1, et seq. for example contacting with e.g.,any of Composition 2, et seq. In some embodiments, the disclosure alsoprovides a method or treating, reducing or preventing plaque with anantibacterially effective amount of a CHC, e.g., any of Complex 1, etseq. for example contacting with e.g., any of Composition 2, et seq.

The disclosure further provides a method of making a complex comprisingCHC, e.g., any of Complex 1, et seq. comprising combining chlorhexidineand sodium cyclamate in aqueous solution, and optionally adding thismixture to ethanol and isolating the crystalline precipitate thusobtained.

The disclosure further provides (i) the use of a CHC, e.g., any ofComplex 1, et seq., to kill bacteria; (ii) the use of a CHC, e.g., anyof Complex 1, et seq., in the manufacture of a composition to killbacteria; (iii) CHC, e.g., any of Complex 1, et seq., for use in killingbacteria; (iv) the use of a CHC, e.g., any of Complex 1, et seq., in themanufacture of a composition to treat, reduce or prevent plaque; (v) theuse of a CHC, e.g., any of Complex 1, et seq., in the manufacture of acomposition to treat, reduce or prevent plaque: and (vi) CHC, e.g., anyof Complex 1, et seq., to treat, reduce or prevent plaque.

It will be understood that, although the CHC may be primarily in theform of a complex, there may be some degree of equilibrium withchlorhexidine and sodium cyclamate precursor materials, so that theproportion of material which is actually in complex compared to theproportion in precursor form may vary depending on the preciseconditions of formulation, concentration of materials, pH, presence orabsence of water, presence or absence of other charged molecules, and soforth.

The composition can include the CHC, e.g., any of Complex 1, et seq.and/or precursors thereof, for example chlorhexidine and sodiumcyclamate. In one embodiment, the CHC is prepared at room temperature bymixing the precursors in an aqueous solution. The in situ formationprovides ease of formulation. The precursors can be used instead offirst having to form the CHC. In another embodiment, the waterpermitting formation of the CHC, e.g., any of Complex 1, et seq. fromthe precursor is water that is present in the oral care composition.

In certain embodiments, the amount of CHC, e.g., any of Complex 1, etseq. in the composition of the disclosure, e.g., any of Compositions 2,et seq., is 0.01 to 40% by weight of the composition. In certainembodiments, precursors, e.g., chlorhexidine and sodium cyclamate, arepresent in amounts such that when combined into the CHC, e.g., any ofComplex 1, et seq., the CHC, e.g., any of Complex 1, et seq. would bepresent in an amount of 0.05 to 10% by weight of the composition. Ineither of these embodiments, the amount of the CHC, e.g., any of Complex1, et seq. can be varied for the desired purpose, such as anantibacterial agent or as an antiplaque agent for extended release. Inother embodiments, the amount of the CHC, e.g., any of Complex 1, etseq. is at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least0.5, at least 1, at least 2, at least 3, or at least 4 up to 10% byweight of the composition. In other embodiments, the amount of the CHC,e.g., any of Complex 1, et seq. is less than 9, less than 8, less than7, less than 6, less than 5, less than 4, less than 3, less than 2, lessthan 1, less than 0.5 to 0.05% by weight of the composition. In otherembodiments, the amounts are 0.05 to 5%, 0.05 to 4%, 0.05 to 3%, 0.05 to2%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2%, 0.5 to 5%, 0.5 to 4%,0.5 to 3%, or 0.5 to 2% by weight of the composition.

In some embodiments, the total amount of chlorhexidine in thecomposition is 0.05 to 10% by weight of the composition. In otherembodiments, the total amount of chlorhexidine is at least 0.1, at least0.2, at least 0.3, at least 0.4, at least 0.5, or at least 1 up to 8% byweight of the composition.

As used herein, an “oral care composition” refers to a composition forwhich the intended use can include oral care, oral hygiene, or oralappearance, or for which the intended method of use can compriseadministration to the oral cavity. The term “oral care composition” thusspecifically excludes compositions which are highly toxic, unpalatable,or otherwise unsuitable for administration to the oral cavity. In someembodiments, an oral care composition is not intentionally swallowed,but is rather retained in the oral cavity for a time sufficient toaffect the intended utility. The oral care compositions as disclosedherein may be used in nonhuman mammals such as companion animals (e.g.,dogs and cats), as well as by humans. In some embodiments, the oral carecompositions as disclosed herein are used by humans. Oral carecompositions include, for example, dentifrice and mouthwash. In someembodiments, the disclosure provides mouthwash formulations.

As used herein, “orally acceptable” refers to a material that is safeand palatable at the relevant concentrations for use in an oral careformulation, such as a mouthwash or dentifrice.

As used herein, “orally acceptable carrier” refers to any vehicle usefulin formulating the oral care compositions disclosed herein. The orallyacceptable carrier is not harmful to a mammal in amounts disclosedherein when retained in the mouth, without swallowing, for a periodsufficient to permit effective contact with a dental surface as requiredherein. In general, the orally acceptable carrier is not harmful even ifunintentionally swallowed. Suitable orally acceptable carriers include,for example, one or more of the following: water, a thickener, a buffer,a humectant, a surfactant, an abrasive, a sweetener, a flavorant, apigment, a dye, an anti-caries agent, an anti-bacterial, a whiteningagent, a desensitizing agent, a vitamin, a preservative, an enzyme, andmixtures thereof.

The carrier represents all other materials in the composition other thanthe CHC, e.g., any of Complex 1, et seq. or the chlorhexidine and sodiumcyclamate. The amount of carrier is then the amount to reach 100% byadding to the weight of the CHC, e.g., any of Complex 1, et seq. or thechlorhexidine and sodium cyclamate.

For oral care compositions, the carrier can be any carrier that is usedfor dentifrices and mouthwashes. The carrier can be in the form of a gelor a solution.

Optional ingredients that can be included in an oral care formulation ofthe compositions of the disclosure include solvents; water-solublealcohols such as C₂₋₈ alcohols including ethanol; humectants (e.g.,glycols including propylene glycol, dipropylene glycol, tripropyleneglycol and mixtures thereof; glycerides including mono-, di- andtriglycerides; and polyols such as sorbitol, xylitol, and propyleneglycol); medium to long chain organic acids, alcohols and esters;surfactants including emulsifying and dispersing agents; structurantsincluding thickeners and gelling agents, for example polymers, abrasivessuch as silicates; and colorants including dyes and pigments.

The compositions can be used in a method to kill bacteria or to treat orprevent plaque by applying the composition to the surface of the teeth(i.e. contacting bacteria or plaque with the composition). In certainembodiments, the application is with the use of a toothbrush. Theapplication is alternatively carried out by swishing a mouthwashcomprising CHC in the oral cavity. For example, in one embodiment, thecombination of the chlorhexidine with the sodium cyclamate increases theduration at which the chlorhexidine is available in the oral cavity,which can then kill bacteria.

Thus, the present disclosure provides (i) a method for killing bacteriain the oral cavity comprising applying to teeth an effective amount of aformulation of any embodiment embraced or specifically described herein,e.g., any of Composition 2 et seq.; and (ii) a method for treating orreducing the formation of plaque comprising applying to teeth aneffective amount of a formulation of any embodiment embraced orspecifically described herein, e.g., any of Compositions 2 et seq.

Unless stated otherwise, all percentages of composition components givenin this specification are by weight based on a total composition orformulation weight of 100%.

The compositions and formulations as provided herein are described andclaimed with reference to their ingredients, as is usual in the art. Aswould be evident to one skilled in the art, the ingredients may in someinstances react with one another, so that the true composition of thefinal formulation may not correspond exactly to the ingredients listed.Thus, it should be understood that the disclosure extends to the productof the combination of the listed ingredients.

EXAMPLES Example 1—Synthesis Chlorhexidine-Cyclamate Complex CHC

An aqueous composition was created according to the formulation detailedin Table 1. It was observed that the chlorhexidine-cyclamate complexformed as a precipitate.

TABLE 1 Material Concentration (wt. %) Chlorhexidine 0.69 Sodiumcyclamate 0.09 Glycerin 9.75 Sodium Fluoride 0.05 Water 84% Tween 200.30 Myacide 0.05 Xylitol 2.0 Sacarina 0.02 Ethyl alcohol 3.0 Mintflavor 0.05

The crystals that precipitated out of the solution were collected andsubjected to further analysis, detailed below.

Example 2: Mass Spectrometric Analysis of CHC

LC-MS analysis was performed using a AB Sciex tandem mass spectrometer(AB Sciex LLC, Framingham, Mass., USA) equipped with an ESI interfaceand Agilent 1260 capillary LC system (Model Agilent 1260, AgilentTechnologies, Palo Alto, Calif., USA). The capillary LC system wasequipped with a capillary binary pump (Model G1376A), a DAD detector(G1315C), a micro vacuum degasser (Model G4225A), a thermostatted columncompartment (Model G1316A. The capillary pump was set under themicro-flow mode. The LC separation was achieved by using an AgilentZorbax SB-Aq column with 2.1 mm i.d.×50 mm dimension and 3.5 μm particlesize (Agilent Technologies, Palo Alto, Calif., USA Part No. 871700-914).

The mobile phase used during the analysis was methanol. The flow ratewas 70 μL/min and the injected volume was 1 μL. The AB Sciex tandem massspectrometer was operated in the positive-ion mode under the followingconditions: nitrogen (>99.99%) was used for curtain gas at 10 psi, ionsource gas 1 and 2 at 10 and 10 psi, respectively. ESI IonSpray voltagewas set at 5.5 kV in ESI interface. The declustering and entrancepotential were set up at 80 and 5.5 v, respectively. The temperature ofthe ionization interface was maintained at 550° C. For total ion count(TIC) mode, the MS screen range was from 50 to 1000 m/z. Data wasacquired with an Analyst software 1.6.2 system (AB Sciex LLC,Framingham, Mass., USA).

The chlorhexidine-cyclamate complex was dissolved into methanol and theconcentration about 200 ppm, which was transferred into the massspectrometer directly for an analysis. Mass spectra of the complex inpositive-ion mode and negative-ion mode are shown in FIGS. 1 and 2 ₁,respectively. FIG. 1 shows chlorhexidine molecular ion represented atm/z 504/506 in a chlorine pattern. Related fragments of chlorhexidineare represented at m/z 335, 252 and 170. Based on molecular analysis,the chlorhexidine adducts (i.e., cyclamate) at M+178 and M+178+178.These findings were confirmed in negative-ion mode as shown in FIG. 2.

To confirm the adduct presence, tandem mass spectroscopy experimentswere conducted in FIGS. 3, 4 and 5. FIG. 3, which was taken innegative-ion mode, shows fragmentation of cyclamate from the parentmolecule represented at m/z 681.9 in FIG. 2. As the molecular weight ofa cyclamate ion is 178.24 g/mol, the presence of the negative ion isclearly shown in FIG. 3. FIG. 4, taken in positive-ion mode, showsfragmentation of the parent molecule represented at m/z 684 in FIG. 1.FIG. 4 illustrates fragmentation of sodium cyclamate at m/z 201.04 andchlorhexidine at m/z 504.2. FIG. 5 was also taken in positive-ion modeand shows the fragmentation of the parent ion represented at m/z 863 ofFIG. 1. FIG. 5 confirms fragmentation of sodium cyclamate at m/z 201.2,chlorhexidine at m/z 505.1, and chlorhexidine bound to two cyclamateions at m/z 863.5.

Example 3: ¹H NMR Analysis of CHC

¹H NMR measurements were performed on samples of CHC at a concentrationof 1 wt. % in a deuterated DMSO solution. All NMR spectra were acquiredon a Bruker Avance spectrometer (Bruker-Biospin, Billerica, Mass., USA)with a 5 mm BBI probe operating at 500.0 MHz for ¹H at 25° C. The ¹H NMRresonance of the compounds were further assigned by means of homonuclearshift correlation 2-dimentional NMR (COSY).

¹H NMR spectroscopy is shown in FIG. 6 and related COSY sequences areshown in FIGS. 7 and 8. Each of these spectra confirmed that bothchlorhexidine and cyclamate exist in the crystal dissolved in DMSO. The¹H NMR chemical shifts corresponding to specific protons ofchlorhexidine and cyclamate were indicated in FIG. 6. Specifically, thepeaks correspond to the chlorhexidine and cyclamate molecules asfollows. According to peak integrals in FIG. 6, the stoichiometric ratiobetween chlorhexidine and cyclamate is 1:2.

Example 4: Determination of Crystal Structure

Single-crystal X-ray data was collected on a Bruker Smart Apexdiffractometer equipped with an Oxford Cryostream low-temperature deviceand a fine-focus sealed-tube X-ray source (Mo KR radiation, λ=0.71073A°, graphite monochromated) operating at 45 kV and 35 mA. The structuredemonstrates the compound crystallizes in P2₁/c space group. Theempirical formula is: [C₂₂H₃₂Cl₂N₁₀][C₆H₁₂NO₃S]₂.H₂O. The detailedstructure is shown in FIG. 9. The chlorhexidine is connected tocyclamate and water by six types of hydrogen bonds. These resultsconfirm the presence of a monohydrate crystalline form.

The data described herein confirms that chlorohexidine is released fromthe inventive complexes in a manner that maximizes its antibacterialactivity.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

Unless otherwise specified, all percentages and amounts expressed hereinand elsewhere in the specification should be understood to refer topercentages by weight. The amounts given are based on the active weightof the material.

The present disclosure has been described with reference to exemplaryembodiments. Although a few embodiments have been shown and described,it will be appreciated by those skilled in the art that changes may bemade in these embodiments without departing from the principles andspirit of preceding detailed description. It is intended that thepresent disclosure be construed as including all such modifications andalterations insofar as they come within the scope of the appended claimsor the equivalents thereof.

1. A chlorhexidine-cyclamate complex having a formula[C₂₂H₃₂Cl₂N₁₀][C₆H₁₂NO₃S]₂.
 2. The chlorhexidine-cyclamate complex ofclaim 1 in crystalline form.
 3. The chlorhexidine-cyclamate complex ofclaim 1, wherein the complex is anhydrous.
 4. Thechlorhexidine-cyclamate complex of claim 1, wherein the complex is inthe form of a hydrate, hemi-hydrate or polyhydrate (e.g., hydrate). 5.The chlorhexidine-cyclamate complex of claim 4, wherein the complex hasthe formula [C₂₂H₃₂Cl₂N₁₀][C₆H₁₂NO₃S]₂.H₂O.
 6. Thechlorhexidine-cyclamate complex of claim 1 that is formed from a mixtureof chlorhexidine and sodium cyclamate in a molar ratio ofchlorhexidine:sodium cyclamate of 1:1 to 1:3 (i.e., 1:2).
 7. Thechlorhexidine-cyclamate complex of claim 1 in crystalline form in aP2₁/c space group.
 8. The chlorhexidine-cyclamate complex of claim 1having a structure wherein a biguanide moiety of the chlorhexidinecation is coordinated by two cyclamate ligands and a water ligand asshown in FIG.
 9. 9. The chlorhexidine-cyclamate complex of claim 1 whichis crystallized in an aqueous solution.
 10. The chlorhexidine-cyclamatecomplex of claim 6 wherein the aqueous solution contains 84 wt % water,3 wt. % ethanol, and 10 wt. % glycerin.
 11. The chlorhexidine-cyclamatecomplex of claim 1 wherein the chlorhexidine-cyclamate complex forms asa precipitate in aqueous solution.
 12. An oral care compositioncomprising the chlorhexidine-cyclamate complex according to claim 1 incombination with an orally acceptable carrier.
 13. The oral carecomposition of claim 12 wherein the chlorhexidine-cyclamate complex isformed, in whole or in part, in situ from chlorhexidine and sodiumcyclamate.
 14. The oral care composition of claim 12 wherein the whereinthe chlorhexidine-cyclamate complex forms as a precipitate in aqueoussolution.
 15. The oral care composition of claim 12 wherein thechlorhexidine-cyclamate complex is present in an amount of 0.01 to 40%by weight of the composition.
 16. The oral care composition of claim 12wherein the composition is in the form of a dentifrice, gel ormouthwash.
 17. A method of killing bacteria comprising contacting thebacteria with a chlorhexidine-cyclamate complex of claim
 1. 18. A methodof treating, reducing or preventing plaque comprising contacting theplaque with a chlorhexidine-cyclamate complex of claim
 1. 19. A methodof making the chlorhexidine-cyclamate complex of claim 1 comprisingcombining chlorhexidine and sodium cyclamate in aqueous solution andprecipitating the complex.
 20. (canceled)